Arylsulfonyl hydroxamic acid derivatives as MMP and TNF inhibitors

ABSTRACT

A compound of the formula ##STR1## wherein R 1 , R 2  R 3 , R 4  R 5 , R 6 , R 7 , R 8 , R 9  and Ar are as defined above, useful in the treatment of a condition seiected from the group consisting of arthritis, cancer, tisuue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other disease characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases involving the production of TNF.

BACKGROUND OF THE INVENTION

This application is a 371 of PCT/IB95/00279 filed Apr. 20, 1995.

The present invention relates to arylsulfonyl hydroxamic acidderivatives which are inhibitors of matrix metalloproteinases or theproduction of tumor necrosis factor (hereinafter also referred to asTNF) and as such are useful in the treatment of a condition selectedfrom the group consisting of arthritis, cancer, tissue ulceration,restenosis, periodontal disease, epidermolysis bullosa, scleritis andother diseases characterized by matrix metalloproteinase activity, aswell as AIDS, sepsis, septic shock and other diseases involving theproduction of TNF.

This invention also relates to a method of using such compounds in thetreatment of the above diseases in mammals, especially humans, and tothe pharmaceutical compositions useful therefor.

There are a number of enzymes which effect the breakdown of structuralproteins and which are structurally related metalloproteases.Matrix-degrading metalloproteinases, such as gelatinase, stromelysin andcollagenase, are involved in tissue matrix degradation (e.g. collagencollapse) and have been implicated in many pathological conditionsinvolving abnormal connective tissue and basement membrane matrixmetabolism, such as arthritis (e.g. osteoarthritis and rheumatoidarthritis), tissue ulceration (e.g. corneal, epidermal and gastriculceration), abnormal wound healing, periodontal disease, bone disease(e.g. Paget's disease and osteoporosis), tumor metastasis or invasion,as well as HIV-infection (J. Leuk. Biol., 52 (2): 244-248, 1992).

Tumor necrosis factor is recognized to be involved in many infectiousand auto-immune diseases (W. Friers, FEBS Letters, 1991, 285, 199).Furthermore, it has been shown that TNF is the prime mediator of theinflammatory response seen in sepsis and septic shock (C. E. Spooner etal., Clinical Immunology and Immunopathology, 1992, 62 S11).

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR2## orthe pharmaceutically acceptable salt thereof, wherein the broken linerepresents an optional double bond;

X is carbon, oxygen or sulfur;

Y is carbon, oxygen, sulfur, sulfoxide, sulfone or nitrogen;

R¹, R² R³, R⁴ R⁵, R⁶, R⁷, R⁸ and R⁹ are selected from the groupconsisting of hydrogen, (C₁ -C₆)alkyl optionally substituted by (C₁-C₆)alkylamino, (C₁ -C₆)alkylthio, (C₁ -C₆)alkoxy, trifluoromethyl, (C₆-C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆ -C₁₀)arylamino, (C₆ -C₁₀)arylthio,(C₆ -C₁₀)aryloxy, (C₅ -C₉)heteroarylamino, (C₅ -C₉)heteroarylthio, (C₅-C₉)heteroaryloxy, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl, (C₃ -C₆)cycloalkyl,hydroxy(C₁ -C₆)alkyl, (C₁ -C₆)alkyl(hydroxymethylene),piperazinyl, (C₆-C₁₀)aryl(C₁ -C₆)alkoxy,(C₅ -C₉)heteroaryl(C₁ -C₆)alkoxy, (C₁-C₆)acylamino, (C₁ -C₆)acylthio, (C₁ -C₆)acyloxy, (C₁ -C₆)alkylsulfinyl,(C₆ -C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfonyl, (C₆ -C₁₀)arylsulfonyl,amino, (C₁ -C₆)alkylamino or ((C₁ -C₆)alkylamino)₂ ; (C₂ -C₆)alkenyl,(C₆ -C₁₀)aryl(C₂ -C₆)alkenyl, (C₅ -C₉)heteroaryl(C₂ -C₆)alkenyl, (C₂-C₆)alkynyl, (C₆ -C₁₀)aryl(C₂ -C₆)alkynyl, (C₅ -C₉)heteroaryl(C₂-C₆)alkynyl, (C₁ -C₆)alkylamino, (C₁ -C₆)alkylthio, (C₁ -C₆)alkoxy,trifluoromethyl, (C₁ -C₆)alkyl (difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁ -C₃)alkyl, (C₆ -C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆ -C₁₀)arylamino, (C₆ -C₁₀)arylthio, (C₆ -C₁₀)aryloxy,(C₅ -C₉)heteroarylamino, (C₅ -C₉)heteroarylthio, (C₅ -C₉)heteroaryloxy,(C₃ -C₆)cycloalkyl, (C₁ -C₆)alkyl(hydroxymethylene), piperidyl, (C₁-C₆)alkylpiperidyl, (C₁ -C₆)acylamino, (C₁ -C₆)acylthio, (C₁-C₆)acyloxy, R¹³ (C₁ -C₆)alkyl wherein R¹³ is (C₁ -C₆)acylpiperazino,(C₆ -C₁₀)arylpiperazino, (C₅ -C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino, (C₆ -C₁₀)aryl(C₁ -C₆)alkylpiperazino,(C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperazino,morpholino,thiomorpholino,piperidino, pyrrolidino, piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅ -C₉)heteroarylpiperidyl,(C₁-C₆)alkylpiperidyl(C₁ -C₆)alkyl,(C₆ -C₁₀)arylpiperidyl(C₁ -C₆)alkyl, (C₅-C₉)heteroarylpiperidyl(C₁ -C₆)alkyl or (C₁ -C₆)acylpiperidyl;

or a group of the formula ##STR3## wherein n is 0 to 6;

Z is hydroxy, (C₁ -C₆)alkoxy or NR¹⁴ R¹⁵ wherein R¹⁴ and R¹⁵ are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl optionally substituted by (C₁ -C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅ -C₉)heteroarylpiperidyl, (C₆ -C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl or (C₃ -C₆)cycloalkyl;piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆ -C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl, (C₁ -C₆)acylpiperidyl, (C₆ -C₁₀)aryl,(C₅-C₉)heteroaryl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl,(C₃ -C₆)cycloalkyl,R¹⁶ (C₂-C₆)alkyl, (C₁ -C₅)alkyl(CHR¹⁶)(C₁ -C₆)alkyl wherein R¹⁶ is hydroxy, (C₁-C₆)acyloxy, (C₁ -C₆)alkoxy, piperazino, (C₁ -C₆)acylamino, (C₁-C₆)alkylthio, (C₆ -C₁₀)arylthio, (C₁ -C₆)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfoxyl, (C₆ -C₁₀)arylsulfoxyl, amino,(C₁ -C₆)alkylamino, ((C₁ -C₆)alkyl)₂ amino, (C₁ -C₆)acylpiperazino, (C₁-C₆)alkylpiperazino, (C₆ -C₁₀)aryl(C₁ -C₆)alkylpiperazino,(C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperazino,morpholino,thiomorpholino,piperidino or pyrrolidino; R¹⁷ (C₁ -C₆)alkyl, (C₁ -C₅)alkyl(CHR¹⁷)(C₁-C₆)alkyl wherein R¹⁷ is piperidyl or (C₁ -C₆)alkylpiperidyl; andCH(R¹⁸)COR¹⁹ wherein R¹⁸ is hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁-C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl, (C₁ -C₆)alkylthio(C₁-C₆)alkyl, (C₆ -C₁₀)arylthio(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfinyl(C₁-C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁ -C₆)alkyl, hydroxy(C₁ -C₆)alkyl,amino(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino(C₁ -C₆)alkyl, ((C₁-C₆)alkylamino)₂ (C₁ -C₆)alkyl, R²⁰ R²¹ NCO(C₁ -C₆)alkyl or R²⁰ OCO(C₁-C₆)alkyl wherein R²⁰ and R²¹ are each independently selected from thegroup consisting of hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyland (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl; and R¹⁹ is R²² O or R²² R²³ Nwherein R²² and R²³ are each independently selected from the groupconsisting of hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl and(C₅ -C₉)heteroaryl(C₁ -C₆)alkyl;

or R¹⁴ and R¹⁵, or R²⁰ and R²¹, or R²² and R²³ may be taken together toform an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,(C₁ -C₆)acylpiperazinyl, (C₁ -C₆)alkylpiperazinyl, (C₆-C₁₀)arylpiperazinyl, (C₅ -C₉)heteroarylpiperazinyl or a bridgeddiazabicycloalkyl ring selected from the group consisting of ##STR4##wherein

r is 1, 2 or 3;

m is 1 or 2;

p is 0 or 1; and

Q is hydrogen, (C₁ -C₃)alkyl, (C₁ -C₆)acyl or (C₁ -C₆)alkoxy carbamoyl;

or R¹ and R², or R³ and R⁴, or R⁵ and R⁶ may be taken together to form acarbonyl;

or R¹ and R², or R³ and R⁴, or R⁵ and R⁶, or R⁷ and R⁸ may be takentogether to form a (C₃ -C₆)cycloalkyl, oxacyclohexyl, thiocyclohexyl,indanyl or tetralinyl ring or a group of the formula ##STR5## whereinR²⁴ is hydrogen, (C₁ -C₆)acyl, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁-C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl or (C₁ -C₆)alkylsulfonyl; and

Ar is (C₆ -C₁₀)aryl or (C₅ -C₉)heteroaryl, each of which may beoptionally substituted by (C₁ -C₆)alkyl, one or two (C₁ -C₆)alkoxy, (C₆-C₁₀)aryloxy or (C₅ -C₉)heteroaryloxy;

with the proviso that R⁷ is other than hydrogen only when R⁸ is otherthan hydrogen;

with the proviso that R⁶ is other than hydrogen only when R⁵ is otherthan hydrogen;

with the proviso that R³ is other than hydrogen only when R⁴ is otherthan hydrogen;

with the proviso that R² is other than hydrogen only when R¹ is otherthan hydrogen;

with the provisio that when R¹, R² and R⁹ are a substituent comprising aheteroatom, the heteroatom cannot be directly bonded to the 2- or 6-positions;

with the proviso that when X is nitrogen, R⁴ is not present;

with the proviso that when X is oxygen, sulfur, sulfoxide, sulfone ornitrogen and when one or more of the group consisting of R¹, R², R⁵ andR⁶, is a substituent comprising a heteroatom, the heteroatom cannot bedirectly bonded to the 4- or 6-positions;

with the proviso that when Y is oxygen, sulfur, sulfoxide, sulfone ornitrogen and when one or more of the group consisting of R³, R⁴, R⁷ andR⁸, are independently a substituent comprising a heteroatom, theheteroatom cannot be directly bonded to the 3- or 5-positions;

with the proviso that when X is oxygen, sulfur, sulfoxide or sulfone, R³and R⁴ are not present;

with the proviso that when Y is nitrogen, R⁴ is not present;

with the proviso that when Y is oxygen, sulfur, sulfoxide or sulfone, R⁵and R⁶ are not present;

with the proviso that when Y is nitrogen, R⁶ is not present;

with the proviso that when the broken line represents a double bond, R⁴and R⁶ are not present;

with the proviso that when R³ and R⁵ are independently a substituentcomprising a heteroatom when the broken line represents a double bond,the heteroatom cannot be directly bonded to positions X and Y;

with the proviso that when either the X or Y position is oxygen, sulfur,sulfoxide, sulfone or nitrogen, the other of X or Y is carbon;

with the proviso that when X or Y is defined by a heteroatom, the brokenline does not represent a double bond;

with the proviso that when R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are alldefined by hydrogen or (C₁ -C⁶)alkyl, either X or Y is oxygen, sulfur,sulfoxide, sulfone or nitrogen, or the broken line represents a doublebond.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "alkoxy", as used herein, includes O-alkyl groups wherein"alkyl" is defined above.

The term "aryl", as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3substituents independently selected from the group consisting of fluoro,chloro, cyano, nitro, trifluoromethyl, (C₁ -C₆)alkoxy, (C₆ -C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy and (C₁ -C₆)alkyl.

The term "heteroaryl", as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic heterocycliccompound by removal of one hydrogen, such as pyridyl, furyl, pyroyl,thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl,benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl,optionally substituted by 1 to 2 substituents independently selectedfrom the group consisting of fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆ -C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy and (C₁-C₆)alkyl.

The term "acyl", as used herein, unless otherwise indicated, includes aradical of the general formula RCO wherein R is alkyl, alkoxy, aryl,arylalkyl or arylalkyloxy and the terms "alkyl" or "aryl" are as definedabove.

The term "acyloxy", as used herein, includes O-acyl groups wherein"acyl" is defined above.

The positions on the ring of formula I, as used herein, are defined asfollows: ##STR6##

The preferred conformation of the compound of formula I includeshydroxamic acid axially disposed in the 2-position.

The compound of formula I may have chiral centers and therefore exist indifferent enantiomeric forms. This invention relates to all opticalisomers and stereoisomers of the compounds of formula I and mixturesthereof.

Preferred compounds of formula I include those wherein Y is oxygen,nitrogen or sulfur.

Other preferred compounds of formula I include those wherein Ar is4-methoxyphenyl or 4-phenoxyphenyl.

Other preferred compounds of formula I include those wherein R⁸ is (C₆-C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅-C₉)heteroaryl(C₁ -C₆)alkyl, carboxylic acid or carboxylic acid (C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R², R³, R⁶,R⁷ and R⁹ are hydrogen.

More preferred compounds of formula I include those wherein Y is carbon,Ar is b 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is (C₆-C₁₀)arylalkynyl or (C₅ -C₉)heteroarylalkynyl.

More preferred compounds of formula I include those wherein Y is oxygen,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is (C₆ -C₁₀)arylalkynylor (C₅ -C₉)heteroarylalkynyl.

More preferred compounds of formula I include those wherein Y is carbon,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is carboxylic acid orcarboxylic acid (C₁ -C₆)alkyl.

More preferred compounds of formula I include those wherein Y is oxygen,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is carboxylic acid orcarboxylic acid (C₁ -C₆)alkyl.

More preferred compounds of formula I include those wherein Y is carbon,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁵ is (C₆ -C₁₀)arylalkynylor (C₅ -C₉)heteroarylalkynyl.

More preferred compounds of formula I include those wherein Y is oxygen,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁵ is (C₆ -C₁₀)arylalkynylor (C₅ -C₉)heteroarylalkynyl.

More preferred compounds of formula I include those wherein Y is carbon,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁵ is carboxylic acid orcarboxylic acid (C₁ -C₆)alkyl.

More preferred compounds of formula I include those wherein Y is oxygen,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁵ is carboxylic acid orcarboxylic acid (C₁ -C₆)alkyl.

More preferred compounds of formula I include those wherein Y is carbon,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁵ is (C₁ -C₆)alkylamino.

More preferred compounds of formula I include those wherein Y is oxygen,Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is (C₁ -C₆)alkylamino.

Specific preferred compounds of formula I include the following:

(2R,3S)-N-hydroxy-3-ethynyl-1-(4-methoxybenzenesulfonyl)-piperidine-2-carboxamide;

(2R,3S)-N-hydroxy-l-(4-methoxybenzenesulfonyl)-3-(5-methoxythiophene-2-yl-ethynyl)-piperidine-2-carboxamide;

(2R,3R)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-(3-pyridin-3-yl-prop-2-ynyl)-piperidine-2-carboxamide;

(2S,3R)-N-hydroxy-4-(4-methoxybenzenesulfonyl)-2-pyridine-3-yl-morpholine-3-carboxamide;

(2S,3R)-N-hydroxy-2-hydroxycarbamoyl-4-(4-methoxybenzenesulfonyl)-morpholine-3-carboxamide;

(2R,3R)-N-hydroxy-2-hydroxycarbamoyl-4-(4-methoxybenzenesulfonyl)-piperidine-2-carboxamide;

(2R,3S)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-(4-phenylpyridine-2-yl)-piperidine-2-carboxamide;

(2S,3R)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-2-(4-phenylpyridine-2-yl)-morpholine-2-carboxamide;

(2R,3S)-N-hydroxy-3-(2-chloro-4-fluorophenyl)-1-(4-methoxybenzenesulfonyl)-piperidine-2-carboxamide;and

(2S,3R)-N-hydroxy-2-(2-chloro4-fluorophenyl)-1-(4-methoxybenzenesulfonyl)-piperidine-3-carboxamide.

The present invention also relates to a pharmaceutical composition for(a) the treatment of a condition selected from the group consisting ofarthritis, cancer, tissue ulceration, restenosis, periodontal disease,epidermolysis bullosa, scleritis and other diseases characterized bymatrix metalloproteinase activity, AIDS, sepsis, septic shock and otherdiseases involving the production of tumor necrosis factor (TNF) or (b)the inhibition of matrix metalloproteinases or the production of tumornecrosis factor (TNF) in a mammal, including a human, comprising anamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof, effective in such treatments or inhibition and apharmaceutically acceptable carrier.

The present invention also relates to a method for the inhibition of (a)matrix metalloproteinases or (b) the production of tumor necrosis factor(TNF) in a mammal, including a human, comprising administering to saidmammal an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating a conditionselected from the group consisting of arthritis, cancer, tissueulceration, restenosis, periodontal disease, epidermolysis bullosa,scleritis and other diseases characterized by matrix metalloproteinaseactivity, AIDS, sepsis, septic shock and other diseases involving theproduction of tumor necrosis factor (TNF) in a mammal, including ahuman, comprising administering to said mammal an amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof, effective intreating such a condition.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, n and Ar in the reaction Schemes and thediscussion that follow are defined as above. ##STR7##

In reaction 1 of Preparation 1, the compound of formula XVI is convertedto the corresponding hydroxy ester compound of formula VI by firstreacting XVI with an arylsulfonylhalide in the presence of triethylamineand an aprotic solvent, such as methylene chloride, tetrahydrofuran ordioxane, at a temperature between about 20° C. to about 30° C.,preferably at room temperature. The compound so formed is furtherreacted with a compound of the formula ##STR8## wherein R²⁵ iscarbobenzyloxy, (C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, in thepresence of sodium hexamethyldisilazane and atetrahydrofuran-dimethylformamide solvent mixture at a temperaturebetween about -20° C. to about 20° C., preferably about 0° C., to formthe hydroxy ester compound of formula VI.

In reaction 1 of Preparation 2, the amine compound of formula XVIII,wherein R²⁵ is as defined above, is converted to the correspondingarylsulfonyl amine compound of formula XVII by (1) reacting XVIII withan arylsulfonylhalide in the presence of triethylamine and an aproticsolvent, such as methylene chloride, tetrahydrofuran, or dioxane, at atemperature between about 20° C. to about 30° C., preferably at roomtemperature, (2) reacting the compound so formed with a compound of theformula ##STR9## in the presence of sodium hexamethyldisilazane and atetrahydrofuran-dimethylformamide solvent mixture at a temperaturebetween about -20° C. to about 20° C., preferably about 0° C., and (3)further reacting the compound so formed with ozone in a methylenechloride-methanol solution at a temperature between about -90° C. toabout -70° C., preferably about -78° C. The unstable ozonide compound soformed is then reacted with triphenylphosphine to form the arylsulfonylamine compound formula XVII. In Reaction 2 of Preparation 2, thearylsulfonyl amine compound of formula XVII is converted to thecorresponding hydroxy ester compound of formula VI by reacting XVII witha compound of the formula ##STR10## wherein W is lithium, magnesium,copper or chromium.

In reaction 1 of Scheme 1, the compound of formula VI, wherein the R²⁵protecting group is carbobenzyloxy, (C₁ -C₆) alkyl, benzyl, allyl ortert-butyl, is converted to the corresponding morpholinone compound offormula V by lactonization and subsequent Claisen rearrangement of thecompound of formula VI. The reaction is facilitated by the removal ofthe R²⁵ protecting group from the compound of formula VI is carried outunder conditions appropriate for that particular R²⁵ protecting group inuse. Such conditions include: (a) treatment with hydrogen and ahydrogenation catalyst, such as 10% palladium on carbon, where R²⁵ iscarbobenzyloxy, (b) saponification where R²⁵ is lower alkyl, (c)hydrogenolysis where R²⁵ is benzyl, (d) treatment with a strong acid,such as trifluoroacetic acid or hydrochloric acid, where R²⁵ istert-butyl, or (e) treatment with tributyltinhydride and acetic acid inthe presence of catalytic bis(triphenylphosphine) palladium (II)chloride where R²⁵ is allyl.

In reaction 2 of Scheme 1, the morpholinone compound of formula V isconverted to the carboxylic acid compound of formula IV by reacting Vwith lithium hexamethyldisilazane in an aprotic solvent, such astetrahydrofuran, at a temperature between about -90° C. to about -70°C., preferably about -78° C. Trimethylsilyl chloride is then added tothe reaction mixture and the solvent, tetrahydrofuran, is removed invacuo and replaced with toluene. The resuling reaction mixture is heatedto a temperature between about 100° C. to about 120° C., preferablyabout 110° C., and treated with hydrochloric acid to form the carboxylicacid compound of formula IV.

In reaction 3 of Scheme 1, the carboxylic acid compound of formula IV isconverted to the corresponding hydroxamic acid compound of formula IIIby treating IV with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and1-hydroxybenztriazole in a polar solvent, such as dimethylformamide,followed by the addition of hydroxylamine to the reaction mixture aftera time period between about 15 minutes to about 1 hour, preferably about30 minutes. The hydroxylamine is preferably generated in situ from asalt form, such as hydroxylamine hydrochloride, in the presence of abase, such as N-methylmorpholine. Alternatively, a protected derivativeof hydroxylamine or its salt form, where the hydroxyl group is protectedas a tert-butyl, benzyl or allyl ether, may be used in the presence of(benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorphosphateand a base, such as N-methylmorpholine. Removal of the hydroxylamineprotecting group is carried out by hydrogenolysis for a benzylprotecting group or treatment with a strong acid, such astrifluoroacetic acid, for a tert-butyl protecting group. The allylprotecting group may be removed by treatment with tributyltinhydride andacetic acid in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride. N,O-bis(4-methoxybenzyl)hydroxylamine may alsobe used as the protected hydroxylamine derivative where deprotection isachieved using a mixture of methanesulfonic acid and trifluoroaceticacid.

In reaction 4 of Scheme 1, the hydroxamic acid compound of formula IIIis converted, if desired, to the corresponding piperidine compound offormula II by treating III with hydrogen and a hydrogenation catayst,such a 10% palladium on carbon.

In reaction 1 of Scheme 2, the arylsulfonylpiperazine compound offormula IX, wherein R²⁶ is carbobenzyloxy, benzyl or carbotertbutyloxy,is converted to the compound of formula VIII by reacting IX with aprotected derivative of hydroxylamine of the formula

    R.sup.27 ONH.sub.2.HCl

wherein R²⁷ is tertbutyl, benzyl or allyl, in the presence ofdicyclohexylcarbodiimide, dimethylaminopyridine and an aprotic solvent,such as methylene chloride. The R²⁶ protecting group is chosen such thatit may be selectively removed in the presence of an without loss of theR²⁷ protecting group, therefore, R²⁶ cannot be the same as R²⁷. Removalof the R²⁶ protecting group from the compound of formula IX is carriedout under conditions appropriate for that particular R²⁶ protectinggroup in use. Such conditions include; (a) treatment with a hydrogen anda hydrogenation catalyst, such as 10% palladium on carbon, where R²⁶ iscarbobenzyloxy, (b) hydrogenolysis where R²⁶ is benzyl or (c) treatmentwith a strong acid, such as trifluoroacetic acid or hydrochloric acidwhere R²⁶ is carbotertbutyloxy.

In reaction 2 of Scheme 2, the compound of formula VIII is converted tothe corresponding hydroxamic acid compound of formula VII, wherein R⁵ ishydrogen or (C₁ -C₆)alkyl, by reacting, if desired, VIII with analkylhalide when R⁵ is (C₁ -C₆)alkyl. Subsequent removal of the R²⁷hydroxylamine protecting group is carried out by hydrogenolysis for abenzyl protecting group or treatment with a strong acid, such astrifluoroacetic acid, for a tert-butyl protecting group. The allylprotecting group may be removed by treatment with tributyltinhydride andacetic acid in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride.

In reaction 1 of Scheme 3, the arylsulfonylamine compound of formulaXII, wherein R²⁵ is as defined above, is converted to the correspondingpiperizine compound of formula XI by reacting XII with a carbodiimideand a base, such as triethylamine. The compound of formula XI is furtherreacted to give the hydroxamic acid compound of formula X according tothe procedure described above in reaction 3 of Scheme 1.

In reaction 1 of Scheme 4, removal of the R²⁸ protecting group andsubsequent reductive amination of the compound of formula XXII, whereinY is oxygen, sulfur or carbon, to give the corresponding imine compoundof formula XXI is carried out under conditions appropriate for thatparticular R²⁹ protecting group in use. Such conditions include thoseused above for removal of the R²⁶ protecting group in reaction 1 ofScheme 2.

In reaction 2 of Scheme 4, the imine compound of formula XXI isconverted to the corresponding piperidine compound of formula XX byreacting XXI with a nucleophile of the formula R² M wherein M islithium, magnesium halide or cerium halide. The reaction is carried outin ether solvents, such as diethyl ether or tetrahydrofuran, at atemperature between about -78° C. to about 0° C., preferably about -70°C.

In reaction 3 of Scheme 4, the sulfonation of the piperidine compound offormula XX to given the corresponding arylsulfonylpiperidine compound offormula XIX is carried out by reacting XX with an arylsulfonylhalide inthe presence of triethylamine and an aprotic solvent, such as metheronechloride, tetrahydrofuran or dioxane, at a temperature between about 20°C. to about 30° C., preferably at room temperature.

In reaction 4 of Scheme 4, the arylsulfonylpiperidine compound offormula XIX is converted to the hydroxamic acid compound of formula XIXaccording to the procedure described above in reaction 3 of Scheme 1.

In reaction 1 of Scheme 5, the compound of formula XXVI, wherein the R²⁹and R³¹ protecting groups are each independently selected from the groupconsisting of carbobenzyloxy, benzyl and carbotertbutyloxy and R³⁰ iscarbobenzyloxy, (C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, is convertedto the corresponding imine compound of formula XXV by the removal of theR²⁹ protecting group and subsequent reductive amination of the compoundof formula XXVI. The R²⁹ protecting group is chosen such that it may beselectively removed in the presence of and without loss of the R³¹protecting group. Removal of the R²⁹ protecting group from the compoundof formula XXVI is carried out under conditions appropriate for thatparticular R²⁹ protecting group in use which will not affect the R³¹protecting group. Such conditions include; (a) treatment with hydrogenand a hydrogenation catalyst, such as 10% palladium on carbon, where R²⁹is carbobenzyloxy and R³¹ is tert-butyl, (b) saponification where R²⁹ is(C₁ -C₆)alkyl and R³¹ is tert-butyl, (c) hydrogenolysis where R²⁹ isbenzyl and R³¹ is (C₁ -C₆) alkyl or tert-butyl, (d) treatment with astrong acid such as trifluoroacetic acid or hydrochloric acid where R²⁹is tert-butyl and R³¹ is (C₁ -C₆)alkyl, benzyl or allyl, or (e)treatment with tributyltinhydride and acetic acid in the presence ofcatalytic bis(triphenylphosphine) palladium (II) chloride where R²⁹ isallyl and R³¹ is (C₁ -C₆)alkyl, benzyl or tert-butyl. The R³⁰ protectivegroup may be selected such that it is removed in the same reaction stepas the R²⁹ protecting group.

In reaction 2 of Scheme 5, the imine compound of formula XXV isconverted to the corresponding compound of formula XXIV by reacting XXVwith a nucleophile of the formula R² M wherein M is lithium, magnesiumhalide or calcium halide. The reaction is carried out in ether solvents,such as diethyl ether or tetrahydrofuran, at a temperature between about-78° C. to about 0° C., preferably about -70° C.

In reaction 3 of Scheme 5, the sulfonation of the piperidine compound offormula XXIV to give the corresponding arylsulfonylpiperidine compoundof formula III is carried out according to the procedure described abovein reaction 3 of Scheme 4.

In reaction 4 of Scheme 5, the arylsulfonylpiperidine compound offormula XXIII is converted to the hydroxamic acid compound of formulaXIV by (1) removing the R³⁰, if needed, and R³¹ protecting groups fromXXIII followed by (2) reacting XXIII according to the proceduredescribed above in reaction 3 of Scheme 1. Removal of the R³⁰ and R³¹protecting groups from the compound of formula XXIII is carried outunder conditions appropriate for that particular R³⁰ and R³¹ protectinggroup in use. Such conditions include those used above for removal ofthe R²⁵ protecting group in reaction 1 of Scheme 1.

Pharmaceutically acceptable salts of the acidic compounds of theinvention are salts formed with bases, namely cationic salts such asalkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium slats, such asammonium, trimethyl-ammonium, diethylammonium, andtris-(hydroxymethyl)-methylammonium slats.

Similarly acid addition salts, such as of mineral acids, organiccarboxylic and organic sulfonic acids e.g. hydrochloric acid,methanesulfonic acid, maleic acid, are also possible provided a basicgroup, such as pyridyl, constitutes part of the structure.

The ability of the compounds of formula I or their pharmaceuticallyacceptable salts (hereinafter also referred to as the compounds of thepresent invention) to inhibit matrix metalloproteinases or theproduction of tumor necrosis factor (TNF) and, consequently, demonstratetheir effectiveness for treating diseases characterized by matrixmetalloproteinase or the production of tumor necrosis factor is shown bythe following in vitro assay tests.

BIOLOGICAL ASSAY Inhibition of Human Collaaenase (MMP-1)

Human recombinant collagenase is activated with trypsin using thefollowing ratio: 10 μg trypsin per 100 μg of collagenase. The trypsinand collagenase are incubated at room temperature for 10 minutes then afive fold excess (50 μg/10 μg trypsin) of soybean trypsin inhibitor isadded.

10 mM stock solutions of inhibitors are made up in dimethyl sulfoxideand then diluted using the following Scheme:

10 mM→120 μM→12 μM→1.2 μM→0.12 μM

Twenty-five microliters of each concentration is then added intriplicate to appropriate wells of a 96 well microfluor plate. The finalconcentration of inhibitor will be a 1:4 dilution after addition ofenzyme and substrate. Positive controls (enzyme, no inhibitor) are setup in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wellsD7-D12.

Collagenase is diluted to 400 ng/ml and 25 μl is then added toappropriate wells of the microfluor plate. Final concentration ofcollagenase in the assay is 100 ng/ml.

Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂) is made as a 5mM stock in dimethyl sulfoxide and then diluted to 20 μM in assaybuffer. The assay is initiated by the addition of 50 μl substrate perwell of the microfluor plate to give a final concentration of 10 μM.

Fluorescence readings (360 nM excitation, 460 nm emission) were taken attime 0 and then at 20 minute intervals. The assay is conducted at roomtemperature with a typical assay time of 3 hours.

Fluorescence vs time is then plotted for both the blank and collagenasecontaining samples (data from triplicate determinations is averaged). Atime point that provides a good signal (the blank) and that is on alinear part of the curve (usually around 120 minutes) is chosen todetermine IC₅₀ values. The zero time is used as a blank for eachcompound at each concentration and these values are subtracted from the120 minute data. Data is plotted as inhibitor concentration vs % control(inhibitor fluorescence divided by fluorescence of collagenasealone×100). IC₅₀ 's are determined from the concentration of inhibitorthat gives a signal that is 50% of the control.

If IC₅₀ 's are reported to be <0.03 μM then the inhibitors are assayedat concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM.

Inhibition of Gelatinase (MMP-2)

Inhibition of gelatinase activity is assayed using theDnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂ substrate (10 μM) under thesame conditions as inhibition of human collagenase (MMP-1).

72 kD gelatinase is activated with 1 mM APMA (p-aminophenyl mercuricacetate) for 15 hours at 4° C. and is diluted to give a finalconcentration in the assay of 100 mg/ml. Inhibitors are diluted as forinhibition of human collagenase (MMP-1) to give final concentrations inthe assay of 30 μM, 3 μM, 0.3 μM and 0.03 μM. Each concentration is donein triplicate.

Fluorescence readings (360 nm excitation, 460 emission) are taken attime zero and then at 20 minutes intervals for 4 hours.

IC₅₀ 's are determined as per inhibition of human collagenase (MMP-1).If IC₅₀ 's are reported to be less than 0.03 μM, then the inhibitors areassayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.003μM.

Inhibition of Stromelysin Activity (MMP-3)

Inhibition of stromelysin activity is based on a modifiedspectrophotometric assay described by Weingarten and Feder (Weingarten,H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase,Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptolidesubstrate Ac-Pro-Leu-Gly-SCH CH₂ CH(CH₃)₂ !CO-Leu-Gly-OC₂ H₅ ! yields amercaptan fragment that can be monitored in the presence of Elliman'sreagent.

Human recombinant prostromelysin is activated with trypsin using a ratioof 1 μl of a 10 mg/ml trypsin stock per 26 μg of stromelysin. Thetrypsin and stromelysin are incubated at 37° C. for 15 minutes followedby 10 μl of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37° C.for 10 minutes at 37° C. to quench trypsin activity.

Assays are conducted in a total volume of 250 μl of assay buffer (200 mMsodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in96-well microliter plates. Activated stromelysin is diluted in assaybuffer to 25 μg/ml. Ellman's reagent (3-Carboxy-4-nitrophenyl disulfide)is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assaybuffer with 50 μl per well yielding at 1 mM final concentration.

10 mM stock solutions of inhibitors are made in dimethyl sulfoxide anddiluted serially in assay buffer such that addition of 50 μl to theappropriate wells yields final concentrations of 3 μM, 0.3 μM, 0.003 μM,and 0.0003 μM. All conditions are completed in triplicate.

A 300 mM dimethyl sulfoxide stock solution of the peptide substrate isdiluted to 15 mM in assay buffer and the assay is initiated by additionof 50 μl to each well to give a final concentration of 3 mM substrate.Blanks consist of the peptide substrate and Ellman's reagent without theenzyme. Product formation was monitored at 405 nm with a MolecularDevices UVmax plate reader.

IC₅₀ values were determined in the same manner as for collagenase.

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenylmercuric acetate) for 1.5 hours, at 37° C. and is diluted to 400 mg/mlin assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mMcalcium chloride, 20 μM zinc chloride, 0.02% brij). Twenty-fivemicroliters of diluted enzyme is added per well of a 96 well microfluorplate. The enzyme is then diluted in a 1:4 ratio in the assay by theaddition of inhibitor and substrate to give a final concentration in theassay of 100 mg/ml.

10 mM stock solutions of inhibitors are made up in dimethyl sulfoxideand then diluted in assay buffer as per the inhibitor dilution schemefor inhibition of human collagenase (MMP-1): Twenty-five microliters ofeach concentration is added in triplicate to the microfluor plate. Thefinal concentrations in the assay are 30 μM, 3 μM, 0.3 μM, and 0.03 μM.

Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂) is prepared asfor inhibition of human collagenase (MMP-1) and 50 μl is added to eachwell to give a final assay concentration of 10 μM. Fluorescence readings(360 nM excitation; 450 emission) are taken at time 0 and every 5minutes for 1 hour.

Positive controls consist of enzyme and substrate with no inhibitor andblanks consist of substrate only.

IC₅₀ 's are determined as per inhibition of human collagenase (MMP-1).If IC₅₀ 's are reported to be less than 0.03 μM, inhibitors are thenassayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003μM.

Inhibition of TNF Production

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit the production of TNF and, consequently, demonstratetheir effectiveness for treating diseases involving the production ofTNF is shown by the following in vitro assay:

Human mononuclear cells were isolated from anti-coagulated human bloodusing a one-step Ficoll-hypaque separation technique. (2) Themononuclear cells were washed three times in Hanks balanced saltsolution (HBSS) with divalent cations and resuspended to a density of2×10⁶ /ml in HBSS containing 1% BSA. Differential counts determinedusing the Abbott Cell Dyn 3500 analyzer indicated that monocytes rangedfrom 17 to 24% of the total cells in these preparations.

180μ of the cell suspension was aliquoted into flate bottom 96 wellplates (Costar). Additions of compounds and LPS (100 ng/ml finalconcentration) gave a final volume of 200 μl. All conditions wereperformed in triplicate. After a four hour incubation at 37° C. in anhumidified CO₂ incubator, plates were removed and centrifuged (10minutes at approximately 250×g) and the supernatants removed and assayedfor TNFα using the R&D ELISA Kit.

For administration to humans for the inhibition of matrixmetalloproteinases or the production of tumor necrosis factor (TNF), avariety of conventional routes may be used including orally,parenterally and topically. In general, the active compound will beadministered orally or parenterally at dosages between about 0.1 and 25mg/kg body weight of the subject to be treated per day, preferably fromabout 0.3 to 5 mg/kg. However, some variation in dosage will necessarilyoccur depending on the condition of the subject being treated. Theperson responsible for administration will, in any event, determine theappropriate dose for the individual subject.

The compounds of the present invention can be administered in a widevariety of different dosage forms, in general, the therapeuticallyeffective compounds of this invention are present in such dosage formsat concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration (intramuscular, intraperitoneal,subcutaneous and intravenous use) a sterile injectable solution of theactive ingredient is usually prepared. Solutions of a therapeuticcompound of the present invention in either sesame or peanut oil or inaqueous propylene glycol may be employed. The aqueous solutions shouldbe suitably adjusted and buffered, preferably at a pH of greater than 8,if necessary and the liquid diluent first rendered isotonic. Theseaqueous solutions are suitable intravenous injection purposes. The oilysolutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

Additionally, it is possible to administer the compounds of the presentinvention topically, e.g., when treating inflammatory conditions of theskin and this may be done by way of creams, jellies, gels, pastes, andointments, in accordance with standard pharmaceutical practice.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

EXAMPLE 1

(+)-(2R*,3R*)-(N-hydroxy)-1-(4-methoxy-benzenesulfonyl)-3-methyl-1,2,3,6-tetrahydropyridine-2-carboxamide.

(a) To a solution of (E)-1-amino-3-pentent-2-ol (2.0 grams, 10.0 mmol)in methylene chloride (50 ml) is added triethylamine (160 μL, 11.0 mmol)followed by 4-methoxybenzenesulfonyl chloride (2.07 grams, 10.0 mmol).The mixture is stirred at room temperature for 12 hours and diluted withethyl acetate. The mixture is washed with water, 10% citric acid, dried(sodium sulfate), filtered and concentrated. The crude product ispurified by silica gel chromatography (elution with 2:1 ethylacetate-hexanes) to provide(N-(2-hydroxy-pent-3-enyl)4-methoxybenzenesulfonamide.

(b) To a solution of(+)-(E)-N-(2-hydroxy-pent-3-enyl)-4-methoxybenzenesulfonamide (1.2grams, 4.42 mmol) in tetrahydrofuran-dimethylformamide (10 mL, ca. 3:1)at 0° C. is added sodium bis(trimethylsilyl)amide (4.9 mL, 1.0M solutionin tetrahydrofuran). After 10 minutes, t-butylbromoacetate (786 mL, 4.83mmol) is added. The mixture is warmed to room temperature, stirred for 1hour and quenched with saturated ammonium chloride solution. The mixtureis extracted with ethyl acetate and the combined extracts are dried(sodium sulfate), filtered and concentrated. The crude product ispurified by silica gel chromatography (elution with 1:1 ethylacetate-hexanes) to provide(2-hydroxy-pent-3-enyl)-(4-methoxybenzenesulfonyl)-amino!-acetic acidt-butyl ester.

(c) To a solution of(+)-(E)-N-(2-hydroxy-pent-3-enyl)-4-methoxybenzenesulfonyl)-amino!-aceticacid t-butyl ester (900 mg, 2.43 mmol) in benzene (10 ml) is addedtrifluoroacetic acid (56 μL, 0.73 mmol). The solution is heated at 80°C. for 3 hours, cooled to room temperature and concentrated to provide(+)-(E)-4-(4-methoxybenzenesulfonyl)-6-propenylmorpholin-2-one which isused without further purification.

(d) To a solution of lithium bis(trimethylsilyl)amide (2.67 mmol, 1.0Min tetrahydrofuran) in tetrahydrofuran (5.0 ml) at -78° C. is added asolution of(+)-(E)-4-(4-methoxybenzenesulfonyl)-6-propenylmorpholine-2-one crudefrom the previous step. After 15 minutes, trimethylsilyl chloride (1.53ml, 12.15 mmol) is added and the mixture warmed to room temperature. Thesolvent is removed (in vacuo) and replaced with toluene (10 ml). Theresulting mixture is heated at 110° C. for 3 hours, cooled to roomtemperature and treated with 1N hydrochloric acid solution. Afterstirring for 10 minutes, the mixture is extracted with ethyl acetate andthe combined extracts are dried (sodium sulfate), filtered andconcentrated. The crude product is purified by silica gel chromatography(elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide(+)-(2R*,3R*)-1-(4-methoxy-benzenesulfonyl)-3-methyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid.

(e) To a sodium of(+)-(2R*,3R*)-1-(4-methoxy-benzensulfonyl)-3-methyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid (100 mg, 0.36 mmol) in dimethylformamide (5 ml.) is addedhydroxybentriazole (53 mg, 0.39 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39mmol). After 1 hour, hydroxylamine hydrochloride (75 mg, 1.08 mmol) isadded followed by triethylamine (150 μL, 1.08 mmol). After stirringovernight, the mixture is diluted with water and extracted with ethylacetate. The combined extracts are dried, filtered and concentrated. Thecrude product is purified by silica gel chromatography (elution with 2:1ethyl acetate-hexanes with 1% acetic acid) to provide(+)-(2R*,3R*)-(N-hydroxy)-1-(4-methoxy-benzenesulfonyl)-3-methyl-1,2,3,6-tetrahydropyridine-2-carboxamideas a white solid. Melting point 173° C. (dec.). Mass spectrum(thermospray): m/Z 326 (m-C(O)N(H)OH, 100%, (m, 7%), (m+H, 30%), (m+NH₄,10%). ¹ H NMR (CDCl₃, 250 MHz, ppm): δ7,72 (d, J=8.9 Hz, 2 H), 7.03 (d,J=8.9 Hz, 2 H), 5.66 (dq, J=13.0, 2.7 Hz, 1 H), 5.45 (dd, 13.0, 1.9 Hz),4.37 (d, 7.0 Hz, 1 H), 4.06-3.82 (m, 2 H), 3.82 (s, 3 H), 3.43-3.30 (m,1 H), 2.62-231 (m, 1 H), 0.97 (d, 7.5 Hz, 3 H).

EXAMPLE 2

N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide

(a) To a solution of glycine t-butyl ester (5.0 grams, 29.82 mmol) inmethylene chloride (50 ml) is added triethylamine (6.65 ml, 62.63 mmol)followed by 4-methoxybenzenesulfonyl chloride (29.82 mmol, 6.2 grams).The solution is stirred for 24 hours, diluted with water and extractedwith ethyl acetate. The combined extracts are dried (sodium sulfate),filtered and concentrated. The crude product is purified by silica gelchromatography (elution with 6:1 hexane-ethyl acetate) to provide(4-methoxybenzenesulfonylamino) acetic acid t-butyl ester.

(b) To a solution of (4-methoxybenzenesulfonylamino) acetic acid t-butylester (3.0 grams, 10 mmol) in tetrahydrofuran-dimethylformamide (mL, ca.3:1) at 0° C. is added sodium bis(trimethylsilyl)amide (10.0 mL, 1.0Msolution in tetrahydrofuran). After 10 minutes,4-bromo-2-methyl-2-butene (1.27 μL, 11.0 mmol) is added. The mixture iswarmed to room temperature, stirred for 1 hour and quenched withsaturated ammonium chloride solution. The mixture is extracted withethyl acetate and the combined extracts are dried (sodium sulfate),filtered and concentrated. The crude product is purified by silica gelchromatography (elution with 1:1 ethyl acetate-hexanes) to provide(4-methoxybenzenesulfonyl)-(3-methyl-but-2-enyl)-amino!-acetic acidt-butyl ester.

(c) Ozone is passed through a solution of(4-methoxybenzenesulfonyl)-(3-methyl-but-2-enyl)-amino!-acetic acidt-butyl ester (2.0 grams, 5.4 mmol) in methylene chloride-methanol (50mL, ca. 1:1) at -78° C. until a blue color persisted. Triphenylphosphine(4.24 grams, 16.2 mmol) is added and the resulting solution is stirredat room temperature for 3 hours. Concentration provided the crudeproduct which is purified by silica gel chromatography (elution with 1:1ethyl acetate-hexanes) to provide(4-methoxybenzenesulfonyl)-(2-oxo-ethyl)-amino!-acetic acid t-butylester.

(d) To a slurry of chromium (II) chloride (1.3 grams, 10.49 mmol) indimethylformamide (20 ml) is added a suspension of nickel (II) chloride(0.026 mmol, 1 mg) in dimethylformamide (1 ml) followed by a mixture of(trans)-β-iodostyrene (1.20 grams, 5.24 mmol) and(4-methoxybenzenesulfonyl)-2-oxo-athyl)-amino!acetic acid t-butyl ester(900 mg, 2.62 mmol) in dimethylformamide (5 ml). The resulting solutionis stirred for three hours, diluted with water and extracted with ethylacetate. The combined extracts are washed with brine, dried (sodiumsulfate), filtered and concentrated. The crude product is purified bysilica gel chromatography (elution with 3:2 hexane-ethyl acetate) toprovide (+)-(E)-(2-hydroxy-4-phenyl-but-3-enyl)-(4-methoxybenzenesulphonyl)-amino!-aceticacid t-butyl ester.

(e) (+)-(E)-(2-hydroxy-4-phenyl-but-3-enyl)-(4-methoxybenzenesulphonyl)-amino!-aceticacid t-butyl ester is subjected to the conditions described in Example1c. The crude product is recrystalized from chloroform to provide(+)-(E)-4-(4-methoxybenzenesulfonyl)-6-styryl-morpholin-2-one.

(f) (+)-(E)-4-(4-methoxybenzenesulfonyl)-6-styryl-morpholin-2-one issubjected to the conditions described in Example 1d. The crude productis purified by silica gel chromatography (elution with 2:1 hexane-ethylacetate with 1% acetic acid) to provide(+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid.

(g)(+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid is subject to the conditions described in Example 1e. The crudeproduct is purified by silica gel chromatography (elution with 1:1hexane-ethyl acetate with 1% acetic acid) to provideN-hydroxy-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamideas a white solid. Melting point 151°-154° C. (dec.). Mass spectrum PBMSw/C.I. (NH₃)!: m/Z 388 (m+NH₄, 100%). ¹ H NMR (CD₃ OD) δ7.75 (d, J=8.5Hz, 2 H), 7.38-7.12 (m, 5 H), 7.04 (d, J=8.5 Hz, 2 H), 5.91 (d, J=8.9Hz, 1 H), 5.28 (d, J=9.9 Hz, 1 H), 4.89 (s, H₂ O), 4.57 (d, 6.8 Hz, 1H), 4.07 (ABq, JAB=18.0 Hz, Δν AB=39.1 Hz, 2 H), 3.85 (o, 3 H), 3.39(bs, CD₃ OD).

EXAMPLE 3

(+)-(2R*-3R*)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-phenyl-piperidine-2-carboxamide

(a) To a solution of(+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylicacid (65 mg, 0.17 mmol) (from Example 20), is added benzylhydroxylaminehydrochloride (32 mg, 0.20 mmol), dicyclohexylcarbodiimide (41 mg, 0.20mmol) and dimethylaminopyridine (27 mg, 0.22 mmol). The resultingmixture is stirred overnight, diluted with ethyl acetate and filteredthrough Celite™ and evaporated. The crude product is purified bychromatography elution with 1:1 hexane-ethyl acetate to provide(+)-(2R*-3R*)-N-benzyloxy-1-4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide.

(b) To a solution of(+)-(2R*-3R*)-N-benzyloxy-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6tetrahydropyridine-2-carboxamide(35 mg, 0.073 mmol) in ethanol (5 ml) is added 10% palladium on carbon(10 mg, 5 mol). The flask is evacuated and backfilled with hydrogen(repeated two times). The reaction mixture is then stirred for 1 hour atwhich time it is filtered through Celite™ and concentrated. The product(+)-2R*-3R*)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-phenylpiperidine-2-carboxamidewas collected as a white solid. Melting point 163° C. (dec). Massspectrum PBMS w/C.I. (NH₃)!: m/Z 390 (m+H₂), (m+NH₄). ¹ H NMR (CD₃ OD)δ7.73 (d, J=8.9 Hz, 2 H), 7.31-737 (m, 5 H), 7.04 (d, 8.9 Hz, 2 H0, 4.89(s, H₂ O), 4.34 (d, J=5.4 Hz,1 H), 3.86 (s, 3 H), 3.74-3.63 (m, 2 H),3.31 (bs, CD₃ OD), 2.99-2.90 (m, 1 H), 2.58-2.52 (m, 1 H), 1.94-1.88 (m,1 H), 1.67-160 (m, 2 H).

EXAMPLE 4

(+)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamidehydrochloride

(a) To a solution of (+)4-benzyloxycarbonyl-2-piperazinecarboxylic acid(1.90 grams, 7.2 mmol) in dioxane-water (10 ml, ca. 1:1) is added 1Nsodium hydroxide solution (15 ml, 15 mmol) followed by4-methoxybenzenesulfonyl chloride. The solution is stirred for 1 hour,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The combined extracts are dried (sodium sulfate), filtered andconcentrated. The crude product is purified by silica gel chromatography(elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide(+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylicacid.

(b) To a solution of(+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylicacid (100 mg, 0.23 mmol) in methylene chloride (5 ml) is addedO-t-butylhydroxylamine hydrochloride (35 mg, 0.28 mmol),dimethylaminopyridine (37 mg, 0.30 mmol), and dicyclohexycarbodiimide(57 mg, 0.28 mmol). After stirring overnight, the reaction is dilutedwith hexanes and the precipitated solid filtered off. The solution isconcentrated and the crude product is purified by silica gelchromatography (elution with 2:1 ethyl acetate-hexanes with 1% aceticacid) to provide(+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxamide.

(c) To a solution of(+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxamide(68 mg, 0.134 mmol), in methanol (6 ml) is added 10% palladium on carbon(7 mg). The flask is evacuated and backfilled with hydrogen (repeated 2times). The reaction mixture is then stirred for 1 hour at which time itis filtered through Celite™ and concentrated. The product(+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamideis used without any further purification.

(d) To a solution of(+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamide(30 mg, in dichloroethane is added ethanol (1 drop). The solution iscooled to -10° C. and hydrogen chloride gase is bubbled through for 5minutes. The reaction is then sealed and stirred for 24 hours at whichtime the volume is reduced to 1/3 by evaporation and the precipitatedsolids are filtered and dried (in vacuo) to give(+)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamidehydrochloride as a white solid. Melting point 167° C. (dec.). Massspectrum (thermospray): m/Z 343 (m+1 100%). ¹ H NMR (CD₃ OD, 250 MHz,ppm): δ7.76 (d, J=8.9 Hz, 2 H), 7.07 (d, J=8.9 Hz, 2 H), 3.87 (bs, H₂ O), 4.19 (d, J=3.3 Hz, 1 H), 3.87 (s, 3 H), 3.58 (bd, J=6.2 Hz, 1 H),3.42 (bd, J=6.1 Hz, 1 H), 3.30 (bs, CD₃ OD), 3.16 (d, J=13.5 Hz, 1 H),2.87 (bd, J=13.3 Hz, 1 H), 2.69 (dd, J=13.3, 3.0 Hz, 1 H), 2.51 (dt,J=12.5, 3.8 Hz, 1 H).

EXAMPLE 5

N-hydroxy-1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxamide

(a) To a solution of (+)-benzyloxycarbonylamino-2-t-butoxycarbonylaminopropionate (2.8 grams, 7.9 mmol) in methylene chloride (25 ml) at0° C. is added a solution of hydrochloric acid (g) dissolved in dioxane(25 ml). The solution is stirred at 0° C. for 4 hours and thenconcentrated. The crude product3-benzyloxycarbonylamino-2-amino-propionic acid methyl esterhydrochloride is used without further purification.

(b) 3-benzyloxycarbonylamino-2-amino-propionic acid methyl esterhydrochloride is subjected to the conditions described in Example 1a.The crude product is purified by silica gel chromatography (elution with1:1 hexane-ethyl acetate) to provide(+)-3-benzyloxycarbonylamino-2-(4-methoxybenzenesulfonylamino)-propionicacid methyl ester.

(c) (+)-3-benzyloxycarbonylamino-2-(4-methoxybenzenesulfonylamino)-propionic acid methyl ester is subjected to theconditions described in Example 1. The crude product is purified bysilica gel chromatography (elution with 3:2 ethyl acetate-hexane) toprovide (+)-3-benzyloxycarbonylamino-2-t-butoxycarbonylmethyl-(4-methoxybenzenesulfonyl)-amino!-propionic acidmethyl ester.

(d) (+)-3-benzyloxycarbonylamino-2-t-butoxycarbonylmethyl-(4-methoxybenzenesulfonyl)-amino!-propionic acidmethyl ester is subjected to the conditions described in Example 4c. Theproduct 3-amino-2-t-butoxycarbonylmethyl-(4-methoxybenzene-sulfonyl)-amino!-propionic acidmethyl ester is used without further purification.

(e) To a solution of 3-amino-2-t-butoxycarbonylmethyl-(4-methoxybenzenesulfonyl)-amino!-propionic acidmethyl ester (2.46 grams, 6.1 mmol) in methylene chloride (20 ml) at 0°C. is added trifluoroacetic acid (5 ml). The solution is stirred at 0°C. for 12 hours and then concentrated. The crude product 3-amino-2-carboxymethyl-(4-methoxybenzenesulfonyl)-amino!-propionic acid methylester trifluoroacetic acid salt is used without further purification.

(f) To a solution of 3-amino-2-carboxymethyl-(4-methoxybenzenesulfonyl)-amino!-propionic acid methylester trfluoracetic acid salt (2.11 grams, 6.1 mmol) in methylenechloride (5 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.76 grams, 9.2 mmol) and triethyamine (3.4 ml, 24.4mmol). The resulting mixture is stirred overnight, diluted with ethylacetate and washed with 1N hydrochlori acid. The organic layer is dried(sodium sulfate), filtered and concentrated. The crude product ispurified by silica gel chromatography (elution with ethyl acetate) toprovide 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acidmethyl ester.

(g) To a solution of1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid methylester. (200 mg, 0.61 mmol) in methanol-tetrahydrofuran-water (5 ml, ca.6:2:1) at 0° C. is added lithium hydroxide (64 mg, 1.53 mmol). Theresulting mixture is stirred for 30 minutes, acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The combinedextracts are dried (sodium sulfate), filtered and concentrated. Thecrude product 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylicacid is used without furtehr purification.

(h) To a solution of1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid (166 mg,0.53 mmol) in methylene chloride (5 ml) is added 0-benzyl hydroxylaminehydrochloride (255 mg, 1.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8mmol) and triethylamine (370 μL 2.65 mmol). The resulting mixture isstirred overnight, diluted with ethyl acetate and washed with 1Nhydrocloric acid. The organic layer is dried (sodium sulfate), filteredand concentrated. The crude product is purified by silica gelchromatography (elution with 5% methanol in methylene chloride) toprovideN-(benzyloxy)-1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxamide.

(i)N-(benzyloxy)-1-(4-methocybenzenesulfonyl)-5-oxo-piperazine-2-carboxamideis subjected to the conditions described in Example 4c to giveN-hydroxy-1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxamide asa white solid. Mass spectrum (thermospray): m/Z 343 (m+H, 60%), (m+NH₄,17%). ¹ H NMR (CD₃ OD), 250 MHz, ppm) δ7.79 (d, J=8.9 Hz, 2 H), 4.90 (s,H₂ O), 4.47 (dd, J=5.0, 3.2 Hz, 1 H), (4.03, s, 2 H), 3.88 (s, 3 H),3.47 (dd, J=13.4, 3.2 Hz, 1 H), 3.35-3.30 (m, 1 H), 3.30 (s, CD₃ OD)

EXAMPLE 6

N-hydroxy-1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxamlde

(a) morpholine-2-carboxylic acid is subjected to the conditionsdescribed in Example 4a to give1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxylic acid.

(b) 1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxylic acid issubjected to the conditions described in example 5h to giveN-benzyloxy-1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxamide.

(c) N-benzyloxy-1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxamide issubjected to the conditions described in Example 4c to giveN-hydroxy-1-(4-methoxybenzenesulfonyl)-morpholin-2-carboxamide as awhite foam. Mass spectrum (thermospray): m/Z 343 (m+H, 100%), α!_(D):+57° (c=0.60, CHCl₃. ¹ H NMR (CDCL₃), 250 MHz, ppm) δ7.78 (bd, J=8.0Hz, 2 H), 7.38 (bs, 1 H), 7.01 (bd, J=8.0 Hz, 2 H), (4.34 (bs, J=2 H),3.87 (s, 3 H), 3.85-3.30 (m, 3 H), 3.30-3.15 (m, 2 H).

We claim:
 1. A compound of the formula ##STR11## or the pharmaceuticallyacceptable salt thereof, wherein X is carbon;Y is sulfer, or oxygen; R¹,R² R³, R⁴, R⁷, R⁸ and R⁹ are selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl optionally substituted by (C₁ -C₆)alkylamino,(C₁ -C₆)alkylthio, (C₁ -C₆)alkoxy, trifluoromethyl, (C₆ -C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆ -C₁₀)arylamino, (C₆ -C₁₀)arylthio, (C₆ -C₁₀)aryloxy,(C₅ -C₉)heteroarylamino, (C₅ -C₉)heteroarylthio, (C₅ -C₉)heteroaryloxy,(C₆ -C₁₀)aryl(C₆ -C₁₀)aryl, (C₃ -C₆)cycloalkyl, hydroxy(C₁ -C₆)alkyl,(C₁ -C₆)alkyl(hydroxymethylene), piperazinyl, (C₆ -C₁₀)aryl(C₁-C₆)alkoxy, (C₅ -C₉)heteroaryl(C₁ -C₆)alkoxy, (C₁ -C₆)acylamino, (C₁-C₆)acylthio, (C₁ -C₆)acyloxy, (C₁ -C₆)alkylsulfinyl, C₆-C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfonyl, (C₆ -C₁₀)arlysulfonyl, amino,(C₁ -C₆)alkylamino or ((C₁ -C₆)alkyl)₂ amino; (C₂ -C₆)alkenyl, (C₆-C₁₀)aryl(C₂ -C₆)alkenyl, (C₅ -C₉)heteroaryl(C₂ -C₆)alkenyl, (C₂-C₆)alkynyl, (C₆ -C₁₀)aryl(C₂ -C₆)alkynyl, (C₅ -C₉)heteroaryl(C₂-C₆)alkynyl, (C₁ -C₆)alkylamino, (C₁ -C₆)alkylthio, (C₁ -C₆)alkoxy,trifluoromethyl, (C₁ -C₆)alkyl (difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁ -C₃)alkyl, (C₆ -C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆ -C₁₀)arylamino, (C₆ -C₁₀)arylthio, (C₆ -C₁₀)aryloxy,(C₅ -C₉)heteroarylamino, (C₅ -C₉)heteroarylthio, (C₅ -C₉)heteroaryloxy,(C₃ -C₆)cycloalkyl, (C₁ -C₆)alkyl(hydroxymethylene), piperidyl, (C₁C₆)alkylpiperidyl, (C₁ -C₆)acylamino, (C₁ -C₆)acylthio, (C₁ -C₆)acyloxy,R¹³ (C₁ C₆)alkyl wherein R¹³ is (C₁ -C₆)acylpiperazino, (C₆-C₁₀)arylpiperazino, (C₅ -C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino, (C₆ -C₁₀)aryl(C₁ -C₆)alkylpiperazino, (C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅ -C₉)heteroarylpiperidyl, (C₁-C₆)alkylpiperidyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylpiperidyl(C₁ -C₆)alkyl,(C₅ -C₉)heteroarylpiperidyl(C₁ -C₆)alkyl or (C₁ -C₆)acylpiperidyl; or agroup of the formula ##STR12## wherein n is 0 to 6: Z is hydroxy, (C₁-C₆)alkoxy of NR¹⁴ R¹⁵ wherein R¹⁴ and R¹⁵ are each independentlyselected from the group consisting of hydrogen, (C₁ -C₆)alkyl optionallysubstituted by (C₁ -C₆)alkylpiperidyl, (C₆ -C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl, (C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆-C₁₀)aryl(C₆ -C₁₀)aryl or (C₃ C₆)cycloalkyl; piperidyl, (C₁-C₆)alkylpiperidyl, (C₆ -C₁₀)arylpiperidyl, (C₅ -C₉)heteroarylpiperidyl,(C₁ -C₆)acylpiperidyl, (C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆C₁₀)aryl(C₆ -C₁₀)aryl, (C₃ -C₆)cycloalkyl, R¹⁶ (C₂ -C₆)alkyl, (C₁-C₅)alkyl(CHR¹⁶)(C₁ -C₆)alkyl wherein R¹⁶ is hydroxy, (C₁ -C₆)acyloxy,(C₁ -C₆)alkoxy, piperazino, (C₁ -C₆)acylamino, (C₁ -C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁ -C₆)alkylsulfinyl, (C₆ -C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfoxyl, (C₆ -C₁₀)arylsulfoxyl, amino, (C₁ -C₆)alkylamino,((C₁ -C₆)alkyl)₂ amino, (C₁ -C₆)acylpiperazino, (C₁ -C₆)alkylpiperazino,(C₆ -C₁₀)aryl(C₁ C₆)alkylpiperazino, (C₅ -C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino, piperidino orpyrrolidino; R¹⁷ (C₁ -C₆)alkyl, (C₁ -C₅)alkyl(CHR¹⁷)(C₁ -C₆)alkylwherein R¹⁷ is piperidyl or (C₁ -C₆)alkylpiperidyl; and CH(R¹⁸)COR¹⁹wherein R¹⁸ is hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅-C₉)heteroaryl(C₁ -C₆)alkyl, (C₁ -C₆)alkylthio(C₁ -C₆)alkyl, (C₆-C₁₀)arylthio(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfonyl(C₁ -C₆)alkyl, (C₆C₁₀)arylsulfonyl(C₁ -C₆)alkyl, hydroxy(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl,(C₁ C₆)alkyamino(C₁ -C₆)alkyl, ((C₁ -C₆)alkyl)₃ amino (C₁ -C₆)alkyl, R²⁰R²¹ NCO(C₁ -C₆)alkyl or R²⁰ OCO(C₁ -C₆)alkyl wherein R²⁰ and R²¹ areeach independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl and (C₅ -C₉)heteroaryl(C₁-C₆)alkyl; and R¹⁹ is R²² O or R²² R²³ N wherein R²² and R²³ are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl and (C₅ -C₉)heteroaryl(C₁-C₆)alkyl; or R¹⁴ and R¹⁵, or R²⁰ and R²¹, or R²² and R²³ may be takentogether to form an azetidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, (C₁ -C₆)acylpiperazinyl, (C₁-C₆)alkylpiperazinyl, (C₆ -C₁₀)arylpiperazinyl, (C₅-C₉)heteroarylpipctazinyl or a bridged diazabicycloalkyl ring selectedfrom the group consisting of ##STR13## wherein r is 1, 2 or 3; m is 1 or2; p is 0 or 1; and Q is hydrogen, (C₁ -C₃)alkyl, (C₁ -C₆)acyl or (C₁-C₆ )alkoxy carbamoyl; or R¹ and R², or R³ and R⁴, may be taken togetherto form a carbonyl; or R¹ and R², or R³ and R⁴, or R⁷ and R⁸ may betaken together to form a (C₃ -C₆)clycloalkyl, oxacyclohexyl,thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula##STR14## wherein R²⁴ is hydrogen, (C₁ -C₆)acyl, (C₁ -C₆)alkyl, (C₆-C₁₀)aryl(C₁ -C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl or (C₁-C₆)alkylsulfonyl; and Ar is (C₆ C₁₀ )aryl or (C₅ -C₉)heteroaryl, eachof which may be optionally substituted by (C₁ C₆)alkyl, one or two (C₁-C₆)alkoxy, (C₆ -C₁₀)aryloxy or (C₅ -C₉)heteroaryloxy; with the provisothat R⁷ is other than hydrogen only when R⁸ is other than hydrogen; withthe proviso that R³ is other than hydrogen only when R⁴ is other thanhydrogen; with the proviso that R² is other than hydrogen only when R¹is other than hydrogen; with the proviso that when R¹, R² and R⁹ are asubstituent comprising a heteroatom, the heteroatom cannot be directlybonded to the 2 or 6-positions; with the proviso that when one or moreof the group consisting of R³, R⁴, R⁷ and R⁸, are independently asubstituent comprising a heteroatom, the heteroatom cannot be directlybonded to the 3- or 5-positions.
 2. A compound according to claim 1,wherein Ar is 4-methoxyphenyl or 4-henoxyphenyl.
 3. A compound accordingto claim 1, wherein R⁸ is (C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆-C₁₀)aryl(C₁ -C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl, carboxylic acidor carboxylic acid (C₁ -C₆)alkyl.
 4. A compound according to claim 1,wherein R², R³, R⁶, R⁷ and R⁹ are hydrogen.
 5. A compound according toclaim 1, wherein Y is oxygen, Ar is 4-methoxyphenyl or 4-phenoxyphenyland R⁸ is (C₆ -C₁₀)arylalkynyl or (C₅ -C₉)heteroarylalkynyl.
 6. Acompound according to claim 1, wherein Y is oxygen, Ar is4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is carboxylic acid orcarboxylic acid (C₁ -C₆)alkyl.
 7. A compound according to claim 1,wherein Y is oxygen, Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R⁸ is(C₁ -C₆)alkylamino.
 8. A compound according to claim 1, wherein saidcompound is selected from the group consistingof:(2S,3R)-N-hydroxy4-(4-methoxybenzenesulfonyl)-2-pyridine-3-yl-morpholine-3-carboxamide;and(2S,3R)-N-hydroxy-2-hydroxycarbamoyl-4-(4-methoxybenzensulfonyl)-morpholine-2-carboxamide.9. A pharmaceutical composition for (a) the treatment of a conditionselected from the group consisting of arthritis, tissue ulceration,restenosis, periodontal disease, epidermolysis bullosa, scleritis andother diseases characterized by matrix metalloproteinase activity,sepsis, septic shock and other diseases involving the production oftumor necrosis factor (TNF) or (b) the inhibition of matrixmetalloproteinases or the production of tumor necrosis factor (TNF) in amammal, comprising an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, effective in such treatmentsor inhibition and a pharmaceutically acceptable carrier.
 10. A methodfor the inhibition of (a) matrix metalloproteinases or (b) theproduction of tumor necrosis factor (TNF) in a mammal, comprisingadministering to said mammal an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof.
 11. A method fortreating a condition selected from the group consisting of arthritis,tissue ulceration, restenosis, periodontal disease, epidermolysisbullosa, and scleritis sepsis, and septic shock in a mammal, comprisingadministering to said mammal an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, effective in treating such acondition.